It is now known that there are two subtypes of angiotensin-II (A-II) receptors, the AT.sub.1 and AT.sub.2 subtypes. Recent studies have shown that in rat brain, A-II receptors are primarily of the AT.sub.2 subtype [Chang et al., Biochem. Biophys. Res. Commun., 171, 813 (1990)]. Agents acting as specific antagonists at these brain A-II receptors are of value in the treatment of a variety of cerebrovascular, cognitive and CNS disorders. For example, the utility of compounds having activity at the AT.sub.2 receptor is disclosed by Bumpus, et al, Hypertension, 17, 720-721 (1991).
Receptors of the AT.sub.2 subtype are also found in female reproductive organs of mammals, including uterus (Dudley, et al, Molecular Pharmacol., 38, 370-377 (1990)) and ovaries (Pucell, et al, Endocrinology, 128, 1947-1959 (1991)). The role of angiotensin II in processes leading to ovulation has been reviewed (Andrade-Gordon, et al, Biochem, Pharmacol., 42, 715-719 (1991)).
In addition, AT.sub.2 receptors are found in neuronal tumor cells (Speth, et al, Peptide Res., 2, 232-239 (1989)) and in transformed human neural cells (Tallant, et al, Hypertension, 17, 1135-1143 (1991)).
Some AT.sub.2 -selective A-II antagonists are known. See for example EP 245,637 and Chang et al., Mol. Pharmacol, 29, 347 (1990) which disclose compounds with structures somewhat different from those of the present application and of rather low potency. Also Whitebread et al., Biochem. Biophys. Res. Commun., 163, 284 (1989) describes a peptide with selective AT.sub.2 antagonist properties but as with all peptides suffers rapid metabolic breakdown and lack of oral activity. Warner-Lambert PCT Patent Publication No. WO 92/05784 discloses certain AT.sub.2 -selective A-II antagonists as having a wide variety of utilities.
Some compounds of chemical structures somewhat similar to those of the compounds of the present invention have been reported in U.S. Pat. Nos. 4,089,958 and 4,138,564. However, they are reported as chemical intermediates only.
Some 1,4-bis(diphenylacetyl)piperazines (without substituents on the piperazine ring carbons) have been disclosed as analgesic, antipyretic, and antiinflammatory agents and CNS depressants (U.S. Pat. No. 3,288,795). The preparation of 1,4-bis (diphenylcarbamoyl)piperazine has been reported [D. E. Rivett and J. F. K. Wilshire, Australian J. Chem., 19, 165 (1966)]. Unsymmetrical 1-acyl-4-(diphenylcarbamoyl)piperazines and 1-acyl-4-(dialkylcarbamoyl) piperazines have also been described [L. Korzycka, et al., Pol. J. Pharmacol. Pharm., 38, 545 (1986); L. Toldy, et al., Acta. Chim. Acad. Sci, Hung., 70, 101 (1971)]. All of these are unsubstituted on the piperazine ring carbons.
Certain 1,4-diacylpiperazine-2-carboxylates and related derivatives in which at least one of the acyl groups is substituted benzoyl have been disclosed as platelet-activating factor antagonists (U.S. Pat. No. 4,923,870 and European Patent Application EP 0,368,670). Methyl 4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylate has been reported as an intermediate (EP 0,368,670), as has methyl 1-(benzyloxycarbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylate and the coresponding acid [C. F. Bigge, et al., Tetrahedron Lett., 30, 5193 (1989).